Diagnosis and Treatment of Marginal Zone Lymphoma

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Supplementum 216 ad Swiss Med Wkly Diagnosis and treatment 2016;146 of marginal zone lymphoma August 9, 2016 The preparation and the publication of this article were supported by Roche Pharma (Schweiz) AG, Reinach, Switzerland, the manufacturer and local distributor of rituximab (MabThera®). The article was evaluated and sent for external peer review by the Swiss Medical Weekly editorial board.

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Peer reviewed article

Diagnosis and treatment of marginal zone lymphoma Sergio Cogliattia*, Mario Bargetzib, Francesco Bertonic,d, Felicitas Hitze, Andreas Lohrif, Ulrich Meyg, Alexandros Papachristofilouh, Christian Tavernai, Emanuele Zuccac*, Christoph Rennerj* a Institute of Pathology, Kantonsspital St. Gallen, Switzerland; b Oncology-Haematology, Kantonsspital Aarau, Switzerland; c IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; d Lymphoma and Genomics Research Programme, IOR Institute of Oncology Research, Bellinzona, Switzer- land; e Oncology-Haematology, Kantonsspital St. Gallen, Switzerland; f Oncology-Haematology, Kantonsspital Baselland, Liestal, Switzerland; g Oncology and Haematology, Kantonsspital Graubuenden, Chur, Switzerland; h Radio-Oncology, Universitätsspital Basel, Switzerland; i Oncology, Kantonsspital Münsterlin- gen, Switzerland; j Onkozentrum Hirslanden & Zürich, Zürich, Switzerland

*SC, EZ, and CR contributed equally to this manuscript

Patients with splenic MZL typically present with en- Summary larged spleens and involvement of the abdominal lymph nodes and bone marrow that displays a rather Marginal zone B-cell lymphoma (MZL) comprises three distinct entities, specific sinusoidal growth pattern. A subset of patients namely extranodal MZL of mucosa-associated lymphoid tissue (MALT lym- shows liver infiltration and leukaemic conversion with phoma), nodal MZL and splenic MZL. Although these three diseases are or without the presence of villous lymphocytes [7]. somewhat related by their histogenetic origins, each displays its own clinical and biological characteristics that are reflected in the individual diagnosis, therapy and outcome. The rarity and heterogeneity of MZL have greatly hampered patient management and therefore no clear guidelines Abbreviations are available on the optimal treatment regimens. This review discusses the BR: bendamustine plus rituximab CHOP: cyclophosphamide, doxorubicin, vincristine and pred- main features, diagnosis and treatment of these MZL subtypes. nisone CLL: chronic lymphocytic leukaemia Key words: marginal zone lymphoma; extranodal marginal zone lymphoma; mucosa-associated lym- CR: complete response phoid tissue; splenic marginal zone lymphoma; nodal marginal zone lymphoma; pathology; diagnosis; treatment; chemotherapy; rituximab CT: computed tomography DLBCL: diffuse large B-cell lymphoma ESMO: European Society for Medical Oncology 18F-FDG: fluorine-18-fluorodeoxyglucose Introduction FISH: fluorescencein-situ hybridisation FL: follicular lymphoma The term “marginal zone B-cell lymphoma” (MZL) re- GELA: Groupe d’Etude des Lymphomes de l’Adulte fers to a group of indolent B-cell lymphomas that origi- GI: gastrointestinal HBV: hepatitis B virus nate from the marginal zone of lymphoid follicles [1]. HCL: hairy cell leukaemia The World Health Organization (WHO) classifies MZL HCV: hepatitis C virus into three distinct entities: extranodal MZL (MALT HIV: human immunodeficiency virus lymphoma), nodal MZL and splenic MZL [2]. Mucosa-as- IFN-α: interferon α sociated lymphoid tissue (MALT) lymphoma is the IGHV: immunoglobulin heavy chain variable region LDH: lactate dehydrogenase most commonly occurring subtype. It can arise at al- LPL: lymphoplasmacytic lymphoma most any extranodal site and is often associated with MALT: mucosa-associated lymphoid tissue chronic antigenic stimulation, either as a result of MCL: mantle cell lymphoma chronic infection (such as gastric Helicobacter pylori MNDA: myeloid cell nuclear differentiation antigen MZL: marginal zone lymphoma infection) or autoimmune diseases [3–6]. MALT lym- NHL: non-Hodgkin’s lymphoma phomas may be subdivided into gastric and non-gas- ORR: overall response rate tric tumours. In a recent survey of 18 US cancer regis- OS: overall survival tries, MALT lymphomas comprised 5%, nodal MZL 2.4% PAS: periodic acid-Schiff and splenic MZL 0.7% of all B-cell lymphomas [6]. PET: positron emission tomography PFS: progression-free survival Primary nodal MZL is rare and the least understood PPI: proton pump inhibitors entity, and has to be clearly distinguished from sec- RT: radiation therapy ondary nodal involvement that arises as a conse- SLL: small lymphocytic lymphoma quence of disseminated extranodal or splenic MZL [7]. WHO: World Health Organization.

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Although these MZL subtypes share some morphologi- is around 60 years, with a slightly higher proportion of cal and immunophenotypic features, their distinct bi- females affected [9]. According to the 2008 WHO classi- ological characteristics have led to their separation fication, MALT lymphoma is by definition an extran- into three individual entities in order to facilitate odal tumour composed of morphologically heteroge- treatment. As a result of the rarity of the disease, there neous marginal zone B cells of varying centrocytoid, are only a few randomised trials testing the various monocytoid or lymphocytoid appearance intermin- treatment options and consequently very little guid- gled with scattered immunoblasts and centroblasts [2]. ance on how to manage MZL. MALT lymphomas are generally indolent and have a This review discusses the clinical features, diagnosis good prognosis with 5-year overall survival (OS) rates and management of each subtype alongside the open over 85% [9]. The most common site of MALT lym- questions that should be considered by the physicians phoma is the stomach (accounting for one third of who treat this complex disease. cases), but the disease also occurs in the salivary glands, ocular adnexa, thyroid, lungs, breast and other tissues. The clinical features and symptoms of MALT MALT lymphoma (extranodal MZL) lymphomas greatly depend on the organ of origin. Pa- Clinical features and diagnosis tients with gastric MALT lymphoma commonly suffer MALT lymphomas often arise in areas that are genu- from nonspecific dyspepsia, nausea, epigastric pain inely devoid of lymphoid tissue, usually following a pe- and eventually from gastrointestinal bleeding. riod of chronic inflammation that results in the accu- One area of uncertainty relates to the optimal staging mulation of B cells [8]. The median age at presentation system that should be used for MALT lymphomas, par-

Figure 1: Representative micrographs of (mucosa associated lymphoid tissue (MALT) lymphomas. A) Low grade gastric MALT lymphoma (overview of a surgical specimen), B) low grade gastric MALT lymphoma with lymphoepithelial lesions C) high-grade blastoid gastric MALT lymphoma, and D) low grade pulmonary MALT lymphoma.

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ticularly for gastric tumours. The Ann Arbor staging phoma (DLBCL) [17]. Table 1 summarises the recom- system has been commonly applied, although it was mended diagnostic work-up procedures for MALT originally designed for use with nodal lymphomas and lymphoma. therefore is not fully applicable to the specific charac- Upon diagnosis of gastric MALT lymphoma, it is im- teristics of extranodal tumours in general or gastric portant to assess the presence of H. pylori, as this will MALT lymphomas in particular [9]. Thus, the modified have an impact on the subsequent therapy. H. pylori is Ann Arbor system is more appropriate [10]. Due to the a Gram-negative bacterium considered to be one of the possibility of disease dissemination to multiple ex- most infectious agents in the stomach and in parts of tranodal sites [11, 12], it may be challenging to detect the gastrointestinal tract, producing inflammation. Al- and identify additional occult lymphoma manifesta- though a wide battery of tests exists for the detection tions. of H. pylori (including serology, urea breath tests, faecal Raderer et al. performed an extensive staging evalua- antigen tests, histology and cultures from biopsy sam- tion in 140 patients, and their findings suggested that ples) [19], it is noteworthy that these are not standard- initially advanced and disseminated disease occurs ised and no guidelines exist as to which test(s) should more frequently in cases where the lymphoma is not be performed. A negative H. pylori histological status primarily localised in the gastrointestinal tract [13]. should be verified using several strategies such as the Due to the possibility of disseminated disease, a thor- urea breath test or the stool antigen and serological ough work-up is recommended for all MALT lympho- tests [20–22]. mas regardless of the site of presentation [14]. A recent meta-analysis of studies published up to February 2014 Pathogenesis on the detection rate of fluorine-18-fluorodeoxyglu- There is a strong association between chronic infec- cose (18F-FDG) positron emission tomography (PET) and tion/inflammation and the pathogenesis of MALT lym- PET / computed tomography (CT) showed that MALT phoma [23, 24]. Of all these, the infectious aetiology of lymphoma is a 18F-FDG-avid tumour in many cases, es- gastric MALT lymphoma has been the most exten- pecially in those with extra-gastric presentation, with sively documented. H. pylori infection is a major causa- a pooled detection rate of 71% (95% confidence interval [CI] 61–80%) [15]. These findings suggest a potential role 18 of F-FDG PET/CT in the initial evaluation, particularly Table 1: Summary of work-up procedures for mucosa- in patients for whom radiotherapy alone is planned to associated lymphoid tissue (MALT) lymphomas. treat localised disease. Diffusion-weighted magnetic All MALT lymphomas [8, 14, 17] resonance imaging has been recently reported to be a Clinical history and physical examination (including lymph very valuable tool, possibly superior to CT and 18F-FDG nodes, eye, ear, nose throat, liver and spleen) PET/CT scans in pre-therapeutic assessment and stag- Laboratory tests ing of MALT lymphoma [16]. Complete blood cell count Today, diagnosis of gastric MALT lymphoma is based Evaluation of liver and kidney function on the histopathological evaluation of gastric biopsies Serum LDH and β2-microglobulin levels Serological HIV, HCV and HBV testing [17] (fig. 1). Immunohistochemically, MALT lymphomas CT scan of the chest, abdomen and pelvis are typically positive for CD20 and CD79a, and negative Bone marrow biopsy for CD5, CD10 and CD23. They may also express CD21 Biopsy of the affected tissue(s) and CD35. However, no specific marker exists for con- Morphological and immunophenotypic (modified Giemsa, clusively identifying MALT lymphomas [18]. The Euro- pan-CK, CD20, CD3, MIB-1) investigations pean Society for Medical Oncology (ESMO) clinical Gastric MALT [17] practice guidelines recommend endoscopy of the oe- Helicobacter pylori serology and/or stool antigen test sophagus, stomach and duodenum accompanied by Endoscopic ultrasound multiple biopsies taken from each of these regions, as Evaluation of t(11;18) /BIRC3(API2)-MALT1 [genetic evaluation is not mandatory for the initial diagnosis] well as from any site with an abnormal appearance. Non-gastric MALT [8, 14] The guidelines also recommend endoscopic ultra- Endoscopic examinations of the gastroduodenal tract sound for assessment of the lymph nodes and depth of to rule out concomitant gastric involvement gastric wall infiltration. Special care should be taken to Endoscopic otorhinolaryngologic examinations rule out histologically the presence of confluent sheets MRI of the orbit of transformed large B cells highlighted by an elevated CT scan of the parotid/salivary glands proliferation rate as measured by Ki67 (MIB-1) immu- CT = computed tomography; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LDH = lactate dehydroge- noreactivity, which represent diffuse large B-cell lym- nase; MRI = magnetic resonance imaging

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tive factor in the development of gastric MALT lym- oping non-gastric MALT lymphomas [23]. Both Hashi- phoma, where it has been hypothesised that the moto thyroiditis and immune sialadenitis as part of lymphoma arises from H. pylori-stimulated B cells. Re- Sjögren syndrome are characterised by the infiltration cent evidence also points towards an infectious origin of B cells in the thyroid and salivary glands, respec- for orbital MALT lymphomas, with the potential cul- tively, followed by progressive lymphoproliferation prit being the intracellular bacterium Chlamydia psit- [23, 28]. However, it is important to note that not all pa- taci [25, 26]. Other infectious agents that have been im- tients infected with H. pylori, C. psittaci or those with plicated in the pathogenesis of MZL include Borrelia autoimmune disorders develop lymphoma, indicating burgdorferi (MALT lymphomas in the skin), Campylo- that other risk factors also play a role in the develop- bacter jejuni (MALT lymphomas in the small intestine) ment of these tumours. There is some evidence indi- [27] and Achromobacter xylosoxidans in the lung [24]. cating that recipients of solid transplants have an in- Autoimmune diseases also increase the risk of devel- creased risk of certain lymphomas (including MZL of MALT-type), suggesting a possible role for immuno- suppression in the aetiology of certain lymphoma subtypes [29, 30]. Table 2: Summary of immunophenotypic and cytogenetic findings in marginal zone B-cell lymphoma (MZL) including differential diagnoses [2, 8, 9, 14, 17, 50, 51, 85]. Cytogenetic, molecular and immunophenotypic MALT lymphomas [18, 24, 87, 89, 97] findings Positive for IgM, CD20, CD79a, CD21, CD35 A common genetic aberration associated with gastric Negative for CD5, CD10, CD23, and cyclin D1 MALT lymphomas is t(11,18)(q21;q21). This translocation t(11;18) translocation in gastric MALT lymphoma in 30–50% of cases results in a fusion between the BIRC3 (API2) gene and Trisomy of chromosomes 3 and 18 the MALT1 gene, producing a chimeric protein with the Inactivation of TNFAIP3 (6q23) ability to enhance cell survival and proliferation by ap- Differential diagnoses [2]: Absence of CD5 is against MCL and SLL/CLL optosis inhibition and activation of the NF-κB pathway, Absence of cyclin D1/SOX11 is against MCL respectively [24, 31]. The 30–50% of patients with gas- Absence of CD10 is against FL tric MALT lymphoma who have this translocation are Nodal MZL [8, 50, 51] more likely to exhibit widely disseminated disease Positive for CD19, CD20, CD79a and PAX5 and are more likely to be H. pylori negative [32]. The Usually negative for CD5, CD10, and CD23 t(14;18)(q32;q21) translocation involving an abnormal Positive for MNDA recombination at the IGH locus on chromosome Trisomy of chromosomes 3 and 18. 14 and the MALT1 locus on chromosome 18 is more Somatic mutations of PTPRD, NOTCH2, MLL2 frequently seen in non-gastric MALT lymphomas [24, Differential diagnoses: 33]. Trisomy of chromosomes 3 and 18 and inactivation FL with marginal zone differentiation: Careful histological review to identify BCL2-negative centroblasts, and centrocytes positive for BCL6 and CD10. FL is often positive for of TNFAIP3 (6q23) occur frequently [18]. High levels of GCET1, LMO2 and HGAL and shows t(14:18) translocations. Stathmin1 may be helpful the FOXP1 protein (a result of chromosomal transloca- for identifying FLs that are negative for BCL2 and/or CD10. tions or copy number changes) is also associated with LPL: clinical features, LPL presents with Waldenström’s macroglobulinaemia, nodal MZL poor prognosis in MALT lymphoma [34, 35]. The molec- presents with lymphadenopathy. Nodal MZL has monocytoid cellular morphology, marginal zone growth pattern, and follicular colonisation. MYD88 L265P mutations ular and cytogenetic aberrations associated with the are more common in LPLs. MZL entities are summarised in table 2. Splenic MZL [2, 44] Positive for CD20, CD79a, co-expression of IgM/IgD Treatment Usually negative for CD5, CD10, CD23, CD43, and CD103 The optimal front-line treatment of patients with Trisomy of chromosomes 3 and 18 MALT lymphoma remains to be determined. The ESMO Deletion of 7q31-q32 Cytogenetic aberrations involving chromosome 8 guidelines emphasise H. pylori eradication therapy for Somatic mutations of NOTCH2, KLF2, MLL2, TP53 all gastric MALT lymphomas, regardless of stage [17]. Frequent use of IGHV1-02 The recommendation for first-line treatment is triple Differential diagnoses [2]: therapy, consisting of the use of a proton pump inhibi- Absence of cyclin D1/SOX11 is against MCL tor (PPI) in combination with clarithromycin and Absence of CD5 is against SLL/CLL amoxicillin (or metronidazole) [17]. The results from Absence of CD103 and annexin A1 against HCL one study suggest that the presence of the t(11;18) trans- Absence of CD10 and BCL6 is against FL location in patients with gastric MALT lymphoma may CLL = chronic lymphocytic leukaemia; FL = follicular lymphoma; LPL = lymphoplasmacytic lymphoma; predict lack of response to H. pylori eradication ther- MALT = mucosa-associated lymphoid tissue; MCL = mantle cell lymphoma; MNDA = myeloid cell nuclear differentiation antigen; SLL = small lymphocytic lymphoma apy [32]. There is still a controversy regarding the use of

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antibiotic therapy for non-gastric MALT lymphomas, Nodal MZL excluding MALT lymphoma of the ocular adnexa, where eradication of C. psittaci with tetracycline has Clinical features and diagnosis been associated with improved response rates and pro- Nodal MZL is a rare entity, accounting for approxi- gression-free survival (PFS) [36, 37]. For gastric MALT mately 2% of lymphomas [6, 48, 49]. The median age at lymphoma, antibiotic therapy is considered worth- diagnosis is ~60 years; however, there is a wide age dis- while even for H. pylori-negative cases, with respect to tribution. Most patients present with stage III or IV dis- false negative testing or the presence of other Helico- ease [50]. There is an equal prevalence in males and fe- bacter species (such as H. heilmannii or H. felis) [17, 38]. males. It is thought to be an indolent disease with a There is no robust evidence-based guidance for the clinical course similar to that of follicular lymphoma treatment of patients who require further therapy be- (FL), but with a highly variable presentation [7]. By defi- yond H. pylori eradication or for those with non-gastric nition, the disease has a nodal origin showing morpho- MALT lymphoma. For patients who do not respond to logical, immunophenotypic, and genetic characteris- H. pylori eradication, those with early-stage gastric tics that overlap with those of extranodal, rather than MALT lymphoma, or those with non-gastric MALT lym- those of splenic MZL (fig. 2). Clinical features at presen- phoma, there is some data supporting the efficacy of tation usually include peripheral lymphadenopathy localised radiation therapy. Disease control can be often involving the head and neck region. Bone mar- achieved by a medium dose of involved-field radiation row involvement is seen in 30–60% of cases. Labora- therapy (24–30 Gy administered within a 3–4 week pe- tory findings show elevated levels of β2-microglobulin riod is suggested by the ESMO guidelines) [17, 39, 40]. and lactate dehydrogenase in roughly one-third of pa- Data from several studies indicate that low-dose radia- tients, and the presence of an M component (~10% of tion therapy (between 2–4 Gy) is effective and well tol- patients), although the proportions vary depending on erated for the treatment of MALT lymphomas [41, 42], the series [50, 51]. Since nodal MZL was only recognised and could be particularly useful for minimising radia- and accepted as a distinct entity by the WHO classification-associated morbidity in certain tissues such as the tion in 2008, data on the clinical features, pathology ocular adnexa [41]. Immunochemotherapy and/or and outcome are limited and vary considerably. chemotherapy are also effective for all stages of MALT In terms of morphology, nodal MZL displays a para-, lymphomas [17]. The combination of rituximab plus peri-, or interfollicular growth pattern in strands and various chemotherapy agents has been shown to yield sheets, which in the beginning excludes reactive lym- good response rates [43–46]. So far, the only immuno- phoid follicles. These may, however, be colonised in chemotherapy regimen that has been tested in a rela- later disease phases. Cytologically, nodal MZL shows tively large randomised study is rituximab plus chlo- small to medium sized lymphoid tumour cells of rambucil. Results from the IELSG-19 study in patients monocytoid, centrocytoid, or lymphocytoid appear- with non-gastric MALT lymphomas and gastric MALT ance, intermingled with tumour blasts in varying lymphomas refractory to prior antibiotic therapy sug- numbers. MZL is characterised by plasmacytoid differ- gested that the combination of chlorambucil plus entiation to varying degrees and may display intranu- rituximab yielded a better outcome compared with ei- clear PAS-positive inclusions (Dutcher bodies). In gen- ther single regimen, although it should be noted that eral, nodal MZL cannot be strictly distinguished from the 5-year OS rate was similar in all three treatment secondary lymph node involvement by primary ex- arms [45]. Results from a recent phase II study by the tranodal or splenic tumours and requires full knowl- Spanish GELTAMO group in 60 patients with MALT edge of the clinical features of these malignancies [52] lymphoma (at any site, and at any stage) showed that (fig. 2). Morphologically, there is a significant overlap the combination of bendamustine plus rituximab between nodal MZL and lymphoplasmacytic lym- yielded good response rates [47]. At 2 years and 4 years, phoma (LPL). However, the latter is more typically asso- event-free survival rates were 93% and 88%, respec- ciated with IgM-paraproteinaemia that manifests as a tively. The ESMO guidelines suggest the use of rituxi- result of Waldenström’s macroglobulinaemia, as it is mab plus chemotherapy for systemic treatment, but characterised by the MYD88 L265P somatic mutation there is no further guidance to indicate which chemo- [53]. MZL also displays a morphological resemblance to therapy agent(s) should be used in combination with FL, inasmuch as on the one hand MZL typically colo- rituximab [17]. nises reactive germinal centres mimicking FL, whereas on the other hand FL may display the feature of a marginal zone differentiation [54] (fig. 2). In cases where the tumour cells have colonised the follicle, neoplastic cells

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Figure 2: Representative micrographs of nodal marginal zone lymphoma (nMZL): A) typical growth pattern of a nMZL (overview H&E staining), B) nMZL showing medium-sized slightly irregularly-shaped tumour cells with features of plasmacytoid differentiation next to sparsely intermingled tumour blasts (high power magnification; H&E staining), C) nMZL displaying a blastoid cytomorphology together with more numerously intermingled tumour blasts (high power magnification; H&E staining), D) nMZL displaying the feature of secondary follicular colonisation (low power magnification; Giemsa staining) in contrast to follicular lymphoma (FL) in fig. 2E, E) low-grade FL with prominent marginal zone B-cell differentiation (low power magnification; Giemsa staining).

express BCL2 and MUM1 but are negative for BCL6 and include full blood and differential counts, complete bio CD10 [55]. Recently, myeloid cell nuclear differentiation chemical tests for liver and kidney function, LDH, β2- antigen (MNDA) has been reported as a potential diag- microglobulin, and protein electrophoresis [57]. Bone nostic marker that may distinguish positive nodal MZL marrow biopsies and chest/abdominal CT scanning are from negative FL [56]. However in such cases FISH analy- also part of the ESMO staging checklist. Although some sis is a more reliable tool and should be performed for reports are optimistic about the use of PET for study- the detection of t(14;18)(q32;q21) chromosomal transloca- ing the extent of the disease [58, 59], this matter is still tion, a rather specific molecular marker for FL. under debate and the ESMO guidelines do not advocate As for the other MZL entities, the optimal diagnostic the use of PET in routine staging and follow-up [57]. A and staging procedures remain to be defined. The stag- summary of the work-up procedures for nodal MZL is ing procedures recommended by the ESMO guidelines shown in table 3.

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Treatment Table 3: Summary of work-up procedures for nodal marginal zone B-cell lymphoma (MZL) [57]. There are no guidelines for the preferred treatment of nodal MZL. The ESMO guidelines recommend that pa- Nodal MZL tients are managed with the same strategies as for FL History and physical examination [57]. In patients with limited disease, localised radiation Bone marrow biopsy Laboratory tests therapy can achieve good tumour control. Current re Complete blood count commendations support the use of a 24 Gy dose applied Evaluation of liver and kidney function markers only to the involved disease sites [66–68]. The use of low- Protein electrophoresis dose (4 Gy) radiation therapy has shown good results in Calcium, LDH, albumin and β2-microglobulin levels the palliative treatment setting [69, 70]. In advanced HCV, HBV and HIV testing stages of the disease, immunochemotherapy is the Helicobacter pylori testing in the case of gastric symptoms main treatment option [57]. A recent study in patients CT scan of the chest, abdomen and pelvis with indolent and mantle cell lymphomas (MCL) (in- Gastroduodenal endoscopy plus ear, nose and throat cluding a subset of patients with nodal MZL) tested evaluation to exclude extranodal disease rituximab plus cyclophosphamide, doxorubicin, vin- CT = computed tomography; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; LDH = lactate dehydroge- cristine and prednisone (R-CHOP) versus bendamustine nase plus rituximab (BR) [71]. The data showed that BR yielded similar outcomes to R-CHOP in terms of PFS, but BR was preferable because it was less toxic [71]. However, owing to the rarity of nodal MZL, there is no robust evidence base from which to select the optimal regimen. Pathogenesis Several reports hint at an association with autoim- Splenic MZL mune disorders including rheumatoid arthritis, viti- ligo, systemic lupus erythematosus, chronic thyroidi- Clinical features and diagnosis tis and Sjögren’s syndrome [51, 60]. Other studies have Splenic MZL accounts for <2% of all lymphomas, but is shown a high hepatitis C virus (HCV) seroprevalence the most common lymphoma originating in the spleen amongst patients with nodal MZL [61–63]. As for the [6, 72]. The median age at presentation is around 65 MALT lymphomas, chronic inflammation may play a years with equal incidence in both genders. Splenic role in the disease aetiology at least in some patients, MZL is believed to be indolent. Median OS is >10 years but the pathogenic mechanisms of nodal MZL remain but around one third of patients have more aggressive unknown. disease, resulting in a shorter OS (4 years). In ~5% of patients, the disease undergoes transformation into Cytogenetic, molecular and immunophenotypic large B-cell lymphoma. The tumour consists mainly of findings small lymphoid cells. It originates in the marginal It is difficult to establish a characteristic immunophe- zone within the white pulp of the spleen and may sec- notypic or cytogenetic profile for nodal MZL. It ex- ondarily involve splenic hilar lymph nodes and bone presses the B-cell markers CD19, CD20, CD79a and PAX5, marrow, where it may show a typical and rather spe- but is usually negative for CD5, CD10, and CD23 [50;51]. cific sinusoidal pattern (fig. 3). The liver is also a fre- IgM/IgD co-expression (a characteristic of splenic MZL) quent site of secondary involvement [72]. Some pa- is found in only a small percentage of nodal cases and tients may become leukaemic but no peripheral its significance is still under debate. Plasmacytic differ- lymphadenopathy is found [2]. Most patients are entiation can be highlighted by expression of plasma- asymptomatic and their disease discovered inciden- cytic markers, such as CD38, CD138 and MUM1 [64]. The tally as anaemia and/or thrombocytopenia in a rou- molecular and cytogenetic aberrations in nodal MZL tine blood count [72]. On the other hand, splenomegaly are summarised in table 2. can be detected upon clinical examination, sometimes The majority of patients with nodal MZL exhibit so- accompanied by anaemia, autoimmune thrombocyto- matic mutations in the IGHV genes, which are more penia and variably by villous lymphocytes in periph- commonly of the IGHV3 and 5 families [65]. There are eral blood [2, 44]. The main clinical symptoms in pa- often trisomies of chromosomes 3 and 18 [2, 18, 44]. The tients with advanced disease are due to splenomegaly arrival at a diagnosis of nodal MZL is usually via exclu- (abdominal discomfort or pain, cytopenias). sion of other less likely diseases with overlapping fea- As for the other MZL entities, arrival at a correct diag- tures (table 2). nosis of splenic MZL requires the integration of clini-

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tometry have recently been established [73, 74]. The tumour cells are positive for cell surface IgM, CD20 and CD79a. They are usually negative for CD5, CD10, CD23 and CD43. It is important to distinguish splenic MZL from hairy cell leukaemia (HCL); in this case, the absence of CD103 and (even more specifically) of annexin A1 weighs against a diagnosis of HCL [75] (table 2). His- tology plays a pivotal role in the diagnostic procedure for splenic MZL (table 2 and table 4). Screening for HCV is important to identify those patients who may benefit from antiviral therapy [72]. As for non-splenic MZL, the patient’s hepatitis B virus (HBV) and human immunodeficiency virus (HIV) status should also be tested. Complete medical history, physical examination, full blood counts, renal and liver biochemical tests, and serum levels of lactate dehydrogenase (LDH) and β2- microglobulin should be performed [73]. Autoimmune diseases are found in 10–15% of patients, and thus should be taken into special consideration [76]. Anaemia, thrombocytopenia, the presence of extrahilar lymphadenopathy, elevated LDH and reduced albumin levels are the main clinical prognostic factors that can be used for risk stratification [76–78]. Tumour infiltration of non-haematopoietic tissues is also an unfa- vourable prognostic factor [41].

Pathogenesis The aetiology is unknown but chronic antigen stimula- Figure 3: Representative micrographs of splenic marginal zone lymphoma (MZL). A) Splenic MZL and B) splenic MZL tion is possibly a trigger for disease onset [79, 80]. In with low-magnification view of the growth pattern. circumscribed populations such as those in southern Italy and parts of the US, splenic MZL occurs more fre- cal, laboratory, imaging and pathological data (table 2 quently in HCV carriers and eradication of the virus re- and table 4). However, a diagnosis of splenic MZL no sults in lymphoma remission [81–84], comparable to longer strictly requires splenectomy [57] since charac- the effect ofH. pylori eradication in gastric MALT lym- teristic features that allow a diagnosis based on bone phoma. marrow examination and peripheral blood flow cy- Cytogenetic, molecular and immunophenotypic findings Pathophysiologically, splenic MZL has yet no known Table 4: Summary of work-up procedures for splenic marginal zone B-cell lymphoma (MZL) [72]. specific genetic marker [85]. The most frequently en- countered cytogenetic abnormalities are trisomy of Splenic MZL chromosomes 3 and 18, and deletion at 7q31.31–q32.3, History and physical examination (particularly spleen) with the latter considered typical of splenic MZL [18, Spleen histology Bone marrow biopsy 86]. Somatic mutations of KLF2 and of genes involved Laboratory tests in the Notch and NF-κB pathways are frequent events Complete blood cell count [87–89]. Other aberrations have also been reported Evaluation of liver and kidney markers (table 2), but these are not present in all patients. Serum LDH, albumin and β2-microglobulin levels About half of patients have somatic mutations in the HCV, HBV and HIV testing IGHV genes, and there is a biased usage of IGHV1-2 and Screening for autoimmunity IGHV3-23 [79, 86]. A large case series recently indicated CT scan of the chest, abdomen and pelvis that one third of splenic MZL patients carry the IGHV1- CT = computed tomography; HBV = hepatitis B virus; HCV = hepatitis C 02 gene, with a strong bias (90% of cases) towards in- virus; HIV = human immunodeficiency virus; LDH = lactate dehydrogenase volvement of the allele 04 polymorphic variant [79],

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suggesting a selection by antigenic stimulation and/or based on alkylating agents such as chlorambucil or cy- an origin from progenitor cells that are adapted to par- clophosphamide [44]. Single-agent fludarabine has also ticular antigenic challenges through selection of spe- been used with some success, although the data come cific VH domains [79]. from case series with small patient numbers [93, 94]. Rituximab, alone or in combination with chemother- Treatment apy, also achieves high overall and complete response There are no treatment recommendations for splenic rates. The ESMO guidelines suggest the use of four MZL. Because the disease is believed to be indolent, a weekly doses of rituximab at 375 mg/m2 as a first-line watch and wait strategy appears to be feasible in many alternative to splenectomy, although the optimal cases. There is no evidence that early intervention treatment regimen and long-term outcome still needs would favour patients with only mild splenomegaly to be established [57]. and no systemic symptoms [72], except for HCV-positive patients, who may benefit even more from an Follow-up for all MZL entities early onset of antiviral therapy [90]. However, one open question is whether patients with a poor prog- Follow-up of non-gastric MALT disease should proceed nostic profile should not receive earlier treatment. The in the same manner as for other indolent lymphomas ESMO guidelines list the criteria indicative for starting (table 5). For H. pylori-positive gastric MALT lymphoma treatment, namely: progressive splenomegaly, pro- patients, eradication of H. pylori cannot be conclu- gressive cytopenias, decrease of haemoglobin <10 g/dl, sively confirmed earlier than 6 weeks after antibiotic platelet count <80 000/µl, and neutrophil count treatment [17]. Endoscopic examinations and a harvest <1000/µl [57]. There are several possible treatment of multiple biopsies 3–6 months after completion of strategies. Splenectomy has been a traditional first-line antibacterial treatment should follow to exclude po- option which can alleviate splenomegaly-related tential residuals [95]. Histological evaluation of re- symptoms and improve cytopenias in the majority of peated biopsies remains an essential part of the follow- patients, resulting in a median PFS of 5 years [91]. How- up procedure. It should be noted that the interpretation ever, removal of the spleen will not influence bone of post-treatment lymphoid infiltrates in gastric biop- marrow or peripheral blood involvement [92]. Chemo- sies is a challenge [17]. ESMO guidelines recommend therapy or immunochemotherapy regimens may be that new biopsies should be compared to previous bi- proposed for patients who are unable or unwilling to opsies using the Groupe d’Etude des Lymphomes de undergo splenectomy. Chemotherapy regimens are l’Adulte (GELA) scoring system [96]. The same procedure of endoscopy plus biopsies should be performed at least twice a year for another 2 years after treatment to monitor stable lymphoma regression. Although it is Table 5: Summary of follow-up and monitoring procedures for the marginal zone B-cell possible to encounter transient local relapses upon his- lymphoma (MZL) entities [57]. tological examination, these are usually self-limiting, MALT (non-gastric and gastric) particularly when there is no H. pylori re-infection [57]. Complete clinical examination (at completion of treatment) Another open question is for how long these patients Laboratory work-up (at completion of treatment) should be followed up. For the time being, the ESMO Radiological or ultrasound examinations (at completion of treatment) guidelines state that in the long run, all gastric MALT Biopsy of any remaining lesions (at completion of treatment) lymphoma patients should be re-evaluated clinically Clinical and endoscopic follow-up every 12–18 months and endoscopically every 12-18 months. It should be Gastric MALT noted that patients with gastric MALT lymphoma have After antibiotic treatment, test for eradication of Helicobacter pylori (stool antigen test, breath test) a reported six-fold higher risk of gastric adenocarci- Endoscopic follow-up with biopsies (2–3 months after treatment, then twice a year for noma compared with the general population [57]. the next 2 years) For patients with splenic or nodal MZL who are asymp- Splenic and nodal MZL tomatic, monitoring should be performed every 6 Complete clinical examination months (table 5). The follow-up procedures should be Blood counts done more frequently (every 4–6 weeks in the first 3 Laboratory work-up months) in patients who have undergone treatment. – For asymptomatic patients, every 6 months Clinicians and pathologists performing the follow-up – For treated patients, at the end of treatment, 4–6 weeks during the first 3 months, then every 6 months on all MZL entities should keep a watchful eye for po- MALT = mucosa-associated lymphoid tissue tential high grade tumour transformation.

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Conclusions 16 Mayerhoefer ME, Karanikas G, Kletter K, et al. Evaluation of diffusion-weighted MRI for pretherapeutic assessment and staging MZL lymphomas are rare and in the majority of cases of lymphoma: results of a prospective study in 140 patients. Clin Cancer Res. 2014;20(11):2984–93. they have an indolent clinical course. The extranodal, 17 Zucca E, Copie-Bergman C, Ricardi U, et al. Gastric marginal zone nodal, and splenic subtypes share some overlapping lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl features but nevertheless represent individual entities. 6):vi144–vi148. Because of their rarity, there are not many randomised 18 Rinaldi A, Mian M, Chigrinova E, et al. Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions trials evaluating therapeutic options, nor guidelines or with an impact on the clinical outcome. Blood. 2011;117(5):1595– protocols for the treatment and follow-up of these pa- 604. tients. Treatment decisions should be a result of collab- 19 Di Rienzo TA, D’Angelo G, Ojetti V, et al. 13C-Urea breath test for the diagnosis of Helicobacter pylori infection. Eur Rev Med Pharmacol oration between the clinician, the pathologist and the Sci. 2013;17(Suppl 2):51–8. patient. 20 Olafsson S, Patel B, Jackson C, Cai J. Helicobacter pylori breath testing in an open access system has a high rate of potentially false negative results due to protocol violations. Helicobacter. Correspondence: Acknowledgements 2012;17(5):391–5. Professor Dr. med. The authors thank Karen Yeow (Biomedicomm Ltd.) for editorial assis- 21 Funakoshi R, Yokoyama H, Kawai N, et al. Effect of pharmaceutical Christoph Renner, tance during the preparation of this manuscript. care in the diagnosis of Helicobacter pylori infection using Onkozentrum Hirslanden, 13C-urea breath test. Yakugaku Zasshi. 2012;132(5):601–7. 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